There is a genetic disease in my maternal line called Adrenoleukedystrophy (also referred to as X-ALD). It is an X-linked disorder that has killed 3 of my male first cousins, at least one of my uncles, and two of my great uncles. The movie “Lorenzo’s Oil” is about a boy who had ALD. Lorenzo’s Oil is an important treatment option; however, there is no cure. Family lore instructed us that females were the carriers and males were the victims of this disease, but it turns out to be more complicated than that.
The disease presents in affected males in one
of two ways:
ALD presents in early childhood and is the most
severe form. Affected children usually develop
normally until they are about 7 years old.
If untreated before a certain age, the boy will rapidly degenerate to a
vegetative state, before which he can go blind and deaf. My Mom’s youngest brother died from the
childhood variant in 1947 at the age of 8. A cousin of mine died at age 13 in 1991.
The other variant, AMN (Adrenomyeloneuropathy) usually develops in
early adulthood, although it can develop later in life. It eventually kills the victim, but not
before they loose the use of their lower limbs. Another first cousin of mine died at 57 years
of age in 2005. Two other male cousins died from AMN in their
20’s.
My maternal grandparents, William and Veronica,
were married in 1910. Two of Veronica’s
brothers seem to have died of ALD, but the disease was not understood back
then. Unbeknownst to her, Grandma was a
carrier. Between 1912 and 1939 my
grandparents had 13 children, 5 boys and 8 girls. The odds are that 50% of these children
either had the disease or were carriers. To date, we can identify 3 of their daughters as being carriers because
they had male descendants who developed one of the two variants of the disease. My grandparents also had at least one son who
died of ALD (Jerry). It is likely that
two other sons (Edward and Wilfred) had ALD, but they died in early childhood
around the time of WWI, and the disease was not understood at that time.
Not every daughter became a carrier, and not every son got the
disease. It was a poorly understood crapshoot. My grandparents had 36 grandchildren. Since we
now know that the children of a carrier mother have a 50/50 chance of getting
the disease, and making the very broad assumption that Edward and Wilfred had
ALD, it is still possible that one more of their children carried the gene. This
is why it is so important that all my living aunts, and my cousins whose mothers
and fathers have died, get tested.
The gene for ALD can act like a terrorist
sleeper cell, hiding for years before revealing itself. For example, my Aunt Rita died in 1958 not realizing she was a carrier. She had three children, a boy who died at 4
months, and two daughters who are still living.
Both daughters had children. K
had a son and two daughters. N had two
sons. Since none of Aunt Rita’s 3 grandsons
developed ALD, no one ever suspected Aunt Rita was a carrier. However, in 2013, 55 years after she died (!)
and 3 generations out, one of her great grandsons, A, was diagnosed at 8 years old. Rita had a daughter, K, who had a daughter,
KY, who is A’s mother. It turns out Rita, K,
and KY were all carriers, but it hid in their genes until A was born.
My mother underwent genetic testing in the
1990’s, after a nephew and 2 grandnephews died from this disease. The results were negative. Now there is more up-to-date information
about the disease, including the fact that the genetic test available in the
1990’s was only 80% accurate. With some
effort I was able to convince Mom’s doctor to get her tested again with the
new (100% accurate) genetic test. The
trick was to convince the doctor to state it was “medically necessary” to
conduct the genetic tests so that insurance would pay for it. He was reluctant. He actually said, “if none of her sons had it then she probably
doesn’t carry the gene”… That is a
genetically naive statement, considering my mother had 7 children and 4 of them
could be female carriers. "Probably" does not cut it when you are dealing with the lives of your descendants. In addition,
two of my three brothers died before they were 40 years old. Remember that one of my cousins did not even
develop AMN until he was in his 40s, and some males carry the gene but do not
develop symptoms. Plus, my mother is 88
years old and living in a nursing home suffering the advanced
stages of Parkinson’s Disease – one of the diseases that can mimic ALD
symptoms. It seemed to me at least
medically necessary to make sure she was not being treated for a disease she
did not have. In fact it is medically
necessary to conduct this test simply to determine if any of her descendants
are at risk. I appealed to him on the
phone, and sent him tons of information on ALD as well as a long genealogy
showing how often it has shown up in our line. Eventually he came around, contacted the experts at Johns Hopkins and
ordered the tests. I appreciate the
fact that he listened and changed his mind when faced with the facts.
The genetic testing was administered through
Johns Hopkins University Hospital in Baltimore. Out-of-pocket it cost a little over $500
because insurance covered most of it. Once
again, her results came back negative.
We are so lucky, and considering the randomness of genetics that is all
it can be: cold, impersonal luck. Good
luck or bad luck.
The information and understanding we had for this
disease was limited prior to A’s diagnosis in 2013; however, that limited understanding
was simple and easy to ignore. We used
to think that only daughters were carriers and only males got the disease. So if none of your brothers developed the
disease it was easy to make the assumption that your family was safe, until A
got it.
A’s mother, KY, wanted the facts, the figures,
and the science in order to help her son.
What she found was disturbing. Apparently,
both men and women can be carriers, not just women. If a
man has the gene then there is 100% chance that he will pass the gene on to his
daughters and zero chance he would pass it on to his sons. If a woman is a carrier then all her
children (male and female) have a 50% chance of inheriting the gene. In addition, some male carriers NEVER show
any symptoms but still pass the gene on to their daughters, AND some female
carriers show symptoms of AMN as they age.
They can be misdiagnosed with diseases like Parkinson’s or MS. So unless modern genetic testing is done on
the oldest living relative in each of Grandma’s children’s families, we will
not know if we carry the gene into future generations or not. Most of my aunts and uncles in this
genealogical line have already passed away.
Unfortunately, that means many of my first cousins still need to be
genetically tested, except the sons of sons of Grandma… because although a
female carrier can pass it on to both her sons and daughters, a male carrier
can only pass it on to his daughters. Are your eyes crossing about now? Maybe this will help:
Males:
- Sons of female carriers have a 50/50 chance of inheriting the gene
- The sons of male carriers/victims are always safe.
- The daughters of male carriers/victims will definitely inherit the gene and are always carriers
- Here is
the kicker: Some male carriers do
not ever display signs of having the disease, but they still have it and they have
100% chance of passing the gene on to their daughters
Females:
- The sons and daughters of female carriers have a 50% chance of carrying the gene
- Almost 50% of female carriers develop some AMN related symptoms as they age
A female carrier would pass the gene on to 50%
of her children. Genetics is a crap
shoot. It could totally skip her sons,
but still be inherited by her daughters – giving the illusion in that
generation of the family being ALD free.
If the carrier daughter only has daughters, her daughters have a 50%
chance and would pass it on to 50% of their children, etc. This is exactly how A developed ALD 55 years
and 3 generations after his great-grandmother died.
I can trace the genealogy of this disease back
to a specific male carrier/victim, my great-great grandfather, Tony Mueller. He would have inherited this disease from his mother. Tony Mueller was born in 1841 and died of AMN at the age of 39 in 1870. He was one of 6 children, so he would not have been the only child who passed this gene down. Odds are that at least 2 more of their children were either carriers or carrier/victims. Anton had 2 daughters and a son with his wife, Susanna. Their son was, of course, genetically exempt. One daughter became a nun. The third child, my Great Grandmother
Catherine, married Frank.
Catherine was a carrier. Catherine
and Frank had 7 children. Two of their
sons died of what the family believes to have been AMN, one at 39 years old and
the other at 19. Her daughter Veronica
(my grandmother) was a carrier. Another
son died at age 15 from a skull fracture.
A second daughter died at age 2 from unknown reasons. Catherine and Frank’s 2 remaining sons seem
not to have inherited the disease.
It is so hard to wrap one’s mind around all
this, but these are the facts. This is
the uncomfortable and complex truth. I
wish it were not true. I wish it were
not so hard to understand or accept.
KY and her mother reached out to every cousin
and aunt who still lived, either directly or through other cousins. She sent a letter outlining the facts. She urged everyone to make sure the oldest
living relative gets tested through the two places in the U.S. who do this
specialized genetic test. She explained
that it was more complicated than we previously thought, i.e., almost no one is
safe unless the genetic testing has been done on the oldest surviving person in their direct line.
In truth, the mathematical odds are clear. Out of 13 children, we know for sure that 4
carried the gene for ALD. It is possible
that two more sons had it, but we can never know for sure if they did. There remains a 50% possibility at least one
more child of William and Veronica inherited that gene. Hopefully the other 50% won out and everyone
else is safe, but we cannot live on hope. The stakes are too high.
What testing needs to be done?
The following is paraphrased from recent updates written by KY:
In 2013, the lab tested A's ABCD1 gene to see the exact genetic change/problem that resulted in his diagnosis. He has a deletion of this gene so testing in other family members must be done by the MLPA - a deletion testing methodology. There are two labs in the USA that do deletion testing on this gene: 1) John Hopkins DNA Diagnostic Lab in Baltimore, Maryland and 2) Emory Genetics Lab in Atlanta, Georgia. A's test was done at John's Hopkins; ideally further family testing should be done in the same lab so they will have A's results as a reference.
In November 2013, A underwent a bone marrow transplant at the U. of Minnesota’s Amplatz Children’s Hospital, which is at the forefront of fighting this terrible disease. It seems to have been successful in stopping further damage. However, his hearing is completely and permanently gone and he is learning American Sign Language. Unfortunately, he has also suffered significant vision loss. The current medications he takes will hopefully stop more damage from occurring, but they cannot correct any damage that occurred prior to the bone marrow transplant. This is why it is so important to know if our children are potential victims. Otherwise, by the time the disease presents, it is too late to stop the damage. In addition, he will remain on hydrocortisone, a steroid, for adrenal insufficiency for the rest of his life. He is 9 years old. California and New York State have recently decided to include ALD testing with the routine screening done on all newborns. Let us hope other states follow suit.
What testing needs to be done?
The following is paraphrased from recent updates written by KY:
In 2013, the lab tested A's ABCD1 gene to see the exact genetic change/problem that resulted in his diagnosis. He has a deletion of this gene so testing in other family members must be done by the MLPA - a deletion testing methodology. There are two labs in the USA that do deletion testing on this gene: 1) John Hopkins DNA Diagnostic Lab in Baltimore, Maryland and 2) Emory Genetics Lab in Atlanta, Georgia. A's test was done at John's Hopkins; ideally further family testing should be done in the same lab so they will have A's results as a reference.
In November 2013, A underwent a bone marrow transplant at the U. of Minnesota’s Amplatz Children’s Hospital, which is at the forefront of fighting this terrible disease. It seems to have been successful in stopping further damage. However, his hearing is completely and permanently gone and he is learning American Sign Language. Unfortunately, he has also suffered significant vision loss. The current medications he takes will hopefully stop more damage from occurring, but they cannot correct any damage that occurred prior to the bone marrow transplant. This is why it is so important to know if our children are potential victims. Otherwise, by the time the disease presents, it is too late to stop the damage. In addition, he will remain on hydrocortisone, a steroid, for adrenal insufficiency for the rest of his life. He is 9 years old. California and New York State have recently decided to include ALD testing with the routine screening done on all newborns. Let us hope other states follow suit.
